This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Specific Aim: Biguanide anti-diabetics as a potential diet restriction mimetics was suggested a while ago (Dilman, 1971;Dilman and Anisimov, 1980) and there are growing evidences that metformin, FDA approved anti-diabetic drug, can modulate life span (Dhahbi et al., 2005;Anisimove et al., 2005). We would like to determine the effects of metformin on life span in fruit flies, Drosophila melanogaster. In preliminary experiments to measure the effects of metformin on lifespan at standard food concentration (10% sugar yeast diet), we found that 5 or 10mM metformin significantly extended lifespan in the standard lab strain, Canton-S. Abstract: Metformin, FDA approved anti-diabetic drug, has long been suggested to have anti-aging effects and to extend lifespan. We showed that metformin can significantly extend lifespan in the fruit fly, Drosophila melanogaster. Median lifespan of flies fed on metformin was increased by up to 33%. Neither reproduction nor food intake was decreased in the flies fed on metformin. Interestingly, feeding rate was slightly increased after metformin treatment. Lifespan extension by metformin was associated with increased resistance to environmental stresses such as starvation and oxidative stress. Work is now proposed to use Drosophila to determine the doses at which metformin functions, and whether the effect of metformin on lifespan depends on nutritional status. In addition, the powerful genetic tools available for Drosophila will be used to determine if metformin's effects are dependent of AMPK signaling. Results from this work will serve as the basis for a larger-scale proposal, and should lead to a better understanding of the mechanisms by which diet restriction extends lifespan.